xe2x80x9cPost-menopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, three major effects of post-menopausal syndrome are the source of the greatest long-term medical concern: Osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, particularly breast and uterine cancer.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This inter-connected network of trabeculae gives lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall structure. In post-menopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in post-menopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of the weight bearing bones such as the femur and the fore-arm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hall-marks of post-menopausal osteoporosis.
At this time, the only generally accepted method for treatment of post-menopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low primarily because estrogen treatment frequently produces undesirable side effects.
Throughout premenopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that post-menopausal women having estrogen replacement therapy have a return of serum lipid levels to concentrations to those of the pre-menopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid level as does estrogen, but would be devoid of some or all of the side-effects and risks associated with estrogen therapy.
The third major pathology associated with post-menopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a post-menopausal women, they are more prevalent in the older, post-menopausal population. Current chemotherapy of these cancers has relied heavily on the use of anti-estrogen compounds such as, for example, tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be contraproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an anti-estrogen compound having negligible or no estrogen agonist properties on reproductive tissues.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, inter alia, post-menopausal syndrome, the present invention provides new compounds, pharmaceutical compositions thereof, and methods of using such compounds for the treatment of post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below.
Uterine fibrosis (uterine fibroid disease) is an old and ever present clinical problem which goes under a variety of names, including uterine fibroid disease, uterine hypertrophy, uterine lieomyomata, myometrial hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue on the wall of the uterus.
This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood but evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition has been produced in rabbits by daily administrations of estrogen for 3 months. In guinea pigs, the condition has been produced by daily administration of estrogen for four months. Further, in rats, estrogen causes similar hypertrophy.
The most common treatment of uterine fibrosis involves surgical procedures both costly and sometimes a source of complications such as the formation of abdominal adhesions and infections. In some patients, initial surgery is only a temporary treatment and the fibroids regrow. In those cases a hysterectomy is performed which effectively ends the fibroids but also the reproductive life of the patient. Also, gonadotropin releasing hormone antagonists may be administered, yet their use is tempered by the fact they can lead to osteoporosis. Thus, there exists a need for new methods for treating uterine fibrosis, and the methods of the present invention satisfy that need.
Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appear to be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue seems to initiate local inflammatory-like responses causing macrophage infiltration and a cascade of events leading to initiation of the painful response. The exact etiology of this disease is not well understood and its treatment by hormonal therapy is diverse, poorly defined, and marked by numerous unwanted and perhaps dangerous side effects.
One of the treatments for this disease is the use of low dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control the symptoms. This use of estrogen can often lead to undesirable side effects and even the risk of endometrial cancer.
Another treatment consists of continuous administration of progestins which induces amenorrhea and by suppressing ovarian estrogen production can cause regressions of the endometrial growths. The use of chronic progestin therapy is often accompanied by the unpleasant CNS side effects of progestins and often leads to infertility due to suppression of ovarian function.
A third treatment consists of the administration of weak androgens, which are effective in controlling the endometriosis; however, they induce severe masculinizing effects. Several of these treatments for endometriosis have also been implicated in causing a mild degree of bone loss with continued therapy. Therefore, new methods of treating endometriosis are desirable.
Smooth muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to a tissue response characterized by an early and late phase. The early phase occurring hours to days after PTCA is due to thrombosis with some vasospasms while the late phase appears to be dominated by excessive proliferation and migration of vascular aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism to the re occlusion of coronary arteries following PTCA, laser angioplasty, and arterial bypass graft surgery. See: xe2x80x9cIntimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplastyxe2x80x9d, Austin et al., Journal of the American College of Cardiology, 8,: 369-375 (August 1985).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by PTCA, atherectomy, laser angioplasty, and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, re occlusion occurs within 3 to 6 months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as agents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonists, steroids, and prostacyclin. These strategies have failed to curb the re occlusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See: xe2x80x9cPrevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a xe2x80x98Magic Bulletxe2x80x99xe2x80x9d, Hermans et al., American Heart Journal, 122,: 171-187 (July 1991).
In the pathogenesis of restenosis, excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall which mediate the proliferation of smooth muscle cells in vascular restenosis.
Agents that inhibit the proliferation and/or migration of smooth aortal muscle cells are useful in the treatment and prevention of restenosis. The present invention provides for the use compounds as smooth aortal muscle cell proliferation inhibitors and, thus inhibitors of restenosis.
The invention provides novel benzothiophenes of the formula (I): 
R1 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94CO(C1-C6 alkyl), xe2x80x94OSO2(C4-C6 alkyl), or xe2x80x94OCOAr where Ar is optionally substituted phenyl;
R2 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94OCO(C1-C6 alkyl), xe2x80x94OSO2(C4-C6 alkyl), xe2x80x94OCOAr where Ar is optionally substituted phenyl, xe2x80x94Cl, or xe2x80x94Br;
R3 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94C1-C4 alkyl, xe2x80x94CN, or xe2x80x94O(C1-C3 alkyl);
R4 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94C1-C4 alkyl, xe2x80x94CN, or xe2x80x94O(C1-C3 alkyl);
R5 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, C1-C4 alkyl, or xe2x80x94O(C1-C3 alkyl);
R6 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, C1-C4 alkyl, or xe2x80x94O(C1-C3 alkyl); with the proviso that R3, R4, R5, and R6 can not all be hydrogen;
Y is xe2x80x94COxe2x80x94, xe2x80x94CHOHxe2x80x94, or xe2x80x94CH2xe2x80x94;
R7 and R8 each are independently C1-C4 alkyl or combine to form, with the nitrogen to which they are attached, 1-piperidinyl, 1-pyrrolidinyl, 1-hexamethyleneimino, or morpholino;
or a pharmaceutically acceptable salt thereof.
A preferred embodiment of this invention is the compound where R1 and R2 each are hydroxy, R5 and R6 each are hydrogen; R3 and R4 each are methyl; and R7 and R8 form a piperidinyl moiety, viz., [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]-3,5-dimethylphenyl] methanone and its hydrochloride salt.
A most preferred embodiment of this invention is the compound where R1 and R2 each are hydroxy, R4, R5, and R6 each are hydrogen; R3 is fluoro; and R7 and R8 form a piperidinyl moiety, viz., [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]-3-fluorophenyl]methanone, and its hydrochloride salt.
The present invention also relates to pharmaceutical acceptable compositions comprising a compound of formula I and pharmaceutically acceptable diluent or carrier.
Included within the scope of compounds of formula I are isomers of asymmetric center.
The present invention further relates to pharmaceutical compositions containing compounds of formula I, optionally containing estrogen or progestin, and the use of such compounds, alone, or in combination with estrogen or progestin, for alleviating the symptoms of post-menopausal syndrome, particularly osteoporosis, cardiovascular related pathological conditions, and estrogen-dependent cancer. As used herein, the term xe2x80x9cestrogenxe2x80x9d includes steroidal compounds having estrogenic activity such as, for example 17xcex2-estradiol, estrone, conjugated estrogen (Premarin(copyright)), equine estrogens, 17xcex2-ethynyl estradiol, and the like. As used herein, the term xe2x80x9cprogestinxe2x80x9d includes compounds having progestational activity such as, for example, progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like.
The current invention relates to the discovery of a new series of benzo[b]thiophenes shown in formula I. These compounds are useful for inhibiting pathological conditions associated with post-menopausal syndrome.
The term xe2x80x9cinhibitxe2x80x9d includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods include both medical therapeutic and/or prophylactic administration, as appropriate.
General terms used in the description of compounds herein described bear their usual meanings. For example, xe2x80x9cC1-C4 alkylxe2x80x9d refers to straight or branched aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, iso-propyl, n-butyl, and the like; and xe2x80x9cC1-C6 alkylxe2x80x9d encompasses the groups included in the definition of xe2x80x9cC1-C4 alkylxe2x80x9d in addition to groups such as pentyl, iso-pentyl, hexyl, and the like. The exception to this terminology is in the case of the sulfonyl derivatives, i.e., xe2x80x9cxe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl)xe2x80x9d, where it is meant to be only; n-butyl, n-pentyl, or n-hexyl.
The term xe2x80x9csubstituted phenylxe2x80x9d refers to a phenyl group having one or more substituents selected from the group consisting of C1-C4 alkyl, C1-C3 alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl. xe2x80x9cC1-C3 alkoxyxe2x80x9d refers a C1-C3 alkyl group attached through an oxygen bridge such as , methoxy, ethoxy, n-propoxy, iso-propoxy.
The compounds of the present invention, i.e., compounds of formula I, may be prepared essentially as described in the U.S. Pat. No. 4,133,814, issued Jan. 9, 1979, U.S. Pat. No. 4,358,593, issued Nov. 9, 1982, U.S. Pat. No. 4,418,068, issued Nov. 29, 1983, U.S. Pat. No. 5,393,763 issued Feb. 28, 1995, and U.S. Pat. No. 5,482,949 issued Jan. 9, 1996 each of which is incorporated by reference.
Briefly, compounds of formula II may be acylated at the 3-position of the benzothiophene nucleus with an activated carboxyl moieties of the compounds of formula III under standard Friedel-Crafts conditions. In general, the acylating conditions would be the use of a Lewis acid such as, AlCl3, BF3, and the like, in an appropriate solvent such a halogenated hydrocarbon, at temperatures from 0-100xc2x0 C. The activated carboxyl moieties of the compounds of formula III are acyl halides, mixed anhydrides, and the like, preferred would be the acid chloride. The compounds of formula II may be prepared in accordance with the methods described in U.S. Pat. No. 4,133,814. It would be understood to those skilled in the art of organic chemistry that the ligands R1 and R2 must be compatible with the acylating conditions to form the compounds of formula I, thus a preferred intermediate would where R1 and R2 are xe2x80x94OMe. The activated carboxyls of the compounds of formula III may be prepared from commercially available carboxylic acids or methods known in the art, with agents such as thionyl chloride. 
where R1 and R2 have their previous meanings. 
and R3, R4, R5, R6, R7, and R8 have their previous meanings, and X is an activating moiety such as xe2x80x94Cl, Br, OAc, and the like.
Other compounds of formula I where R1 and R2 are esters or sulfonates can be derived from de-methylating the dimethoxy compound with AlCl3, BCl3, etc., and acylating with the appropriate acyl or sulfonyl moiety.
An alternate method of preparing the compounds of formula I, especially preferred for the preparation of the preferred compounds of this invention, would be to acylate the 3-position on a compound of formula II with a compound of formula IV, using standard Friedel-Crafts conditions, to form the compounds of formula V. The 4-OMe group of the benzoyl moiety may be selectively removed using NaSEt to form the compounds of formula VI. The compounds of formula VI may O-alkylated with the compounds of formula VII with an inorganic base such K2CO3, Cs2CO3, and the like, to form the final compounds of formula I. 
where R3, R4, R5, and R6 have their previous meanings. 
where R1, R2, R3, R4, R5, and R6 have their previous meanings. 
where R1, R2, R3, R4, R5, and R6 have their previous meanings. 
where R7 and R8 have their previous meanings.
Other compounds of formula I where Y is a carbinol or methylene can be prepared in the following manner.
Reduction of the carbonyl to the carbinol and further to the methylene can be accomplished step-wise or form the carbonyl to the methylene in a single step.
Briefly, the carbonyl compound can be reduced to the carbinol with LiAlH4, NaBH4, or the like in appropriate solvents such chlorocarbons, THF, ether, etc. at temperatures of 0-30xc2x0 C. The carbinol may be reduced to the methylene with silanes, e.g., triethylsilane, in appropriate solvents such as, methylene chloride or THF with a strong acid such as trifluoroacetic acid, at ambient temperatures. Alternatively, the carbonyl compound may be reduced directly to the methylene by using LiAlH4 in a high boiling solvent such as propylbenzene at reflux temperatures.